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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Investigating the Efficacy and Safety of Mesalamine 4 g Extended Release Granules (Sachet) for the Induction of Clinical and Endoscopic Remission in Active, Mild to Moderate Ulcerative Colitis

    Summary
    EudraCT number
    		 2015-002557-35
    Trial protocol
    		 BE   HU   LV   BG  
    Global end of trial date
    03 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Apr 2019
    First version publication date
    12 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    000174
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02522767
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ferring International Pharmascience Center US, Inc.
    Sponsor organisation address
    100 Interpace Parkway, Parsippany, NJ, United States, 07054
    Public contact
    Global Clinical Compliance, Ferring Pharmaceuticals, DK0-Disclosure@ferring.com
    Scientific contact
    Global Clinical Compliance, Ferring Pharmaceuticals, DK0-Disclosure@ferring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate efficacy of mesalamine 4 g extended release granules (sachet) once daily (QD) in the induction of clinical and endoscopic remission versus placebo in subjects with active, mild to moderate ulcerative colitis (UC)
    Protection of trial subjects
    The trial was performed in accordance with the Declaration of Helsinki and its amendments in force at the initiation of the trial, in compliance with the approved protocol and its amendments, Good Clinical Practice and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    Ukraine: 114
    Country: Number of subjects enrolled
    United States: 27
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Latvia: 6
    Worldwide total number of subjects
    228
    EEA total number of subjects
    17
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    212
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 71 sites in 10 countries (Bulgaria, Canada, Hungary, Latvia, Mexico, Russia, Serbia, Switzerland, Ukraine, and United States) recruited subjects to this trial between October 2015 to November 2017, the last subject completed last visit in April 2018.

    Pre-assignment
    Screening details
    		 A total of 411 subjects were screened, of which 228 subjects were randomised in a 1:1 ratio to either mesalamine or placebo group (114 subjects each), for 8 weeks double-blind treatment. Subjects who completed 8 weeks but failed to meet the defined criteria for remission received open-label treatment with mesalamine for additional 8 weeks.

    Period 1
    Period 1 title
    Double-blind treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mesalamine
    Arm description
    		 Mesalamine 4 g extended release granules (sachet), administered orally QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mesalamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses (4 g extended release granules, sachet) were administered QD at least 1 hour before or at least 2 hours after a meal at approximately the same time each day. The sachet was emptied on the tongue and swallowed with at least 8 ounces (240 mL) of water.

    Arm title
    		 Placebo
    Arm description
    		 Placebo 4 g to match mesalamine extended release granules, administered orally QD
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses (4 g placebo sachet matching mesalamine extended release granules, sachet) were administered QD at least 1 hour before or at least 2 hours after a meal at approximately the same time each day. The sachet was emptied on the tongue and swallowed with at least 8 ounces (240 mL) of water.

    Number of subjects in period 1
    		Mesalamine Placebo
    Started
    114
    114
    Completed
    103
    90
    Not completed
    11
    24
         Consent withdrawn by subject
    8
    11
         Adverse event, non-fatal
    1
    10
         Protocol violation
    -
    1
         Protocol deviation
    1
    -
         Lost to follow-up
    1
    -
         Lack of efficacy
    -
    2
    Period 2
    Period 2 title
    Open-Label
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Mesalamine (Open-Label)
    Arm description
    		 Mesalamine 4 g extended release granules (sachet), administered orally QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mesalamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses (4 g extended release granules, sachet) were administered QD at least 1 hour before or at least 2 hours after a meal at approximately the same time each day. The sachet was emptied on the tongue and swallowed with at least 8 ounces (240 mL) of water.

    Number of subjects in period 2 [1]
    		Mesalamine (Open-Label)
    Started
    170
    Completed
    158
    Not completed
    12
         Consent withdrawn by subject
    5
         Adverse event, non-fatal
    3
         Protocol violation
    1
         Lost to follow-up
    1
         Lack of efficacy
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects provided their consent to receive additional 8 weeks open-label treatment with mesalamine.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mesalamine
    Reporting group description
    		 Mesalamine 4 g extended release granules (sachet), administered orally QD

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 4 g to match mesalamine extended release granules, administered orally QD

    Reporting group values
    		 Mesalamine Placebo Total
    Number of subjects
    		 114 114 228
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 107 105 212
        From 65-84 years
    		 7 9 16
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.2 ± 13.09 43.9 ± 13.68 -
    Gender categorical
    Units: Subjects
        Female
    		 57 64 121
        Male
    		 57 50 107
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 3 5 8
        Asian
    		 1 2 3
        Black or African American
    		 5 4 9
        White
    		 105 103 208
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 9 9 18
        Not Hispanic or Latino
    		 105 105 210
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 24.68 ± 4.546 24.63 ± 4.578 -
    Stool frequency score
    Units: points
        arithmetic mean (standard deviation)
    		 1.6 ± 0.81 1.8 ± 0.78 -
    Rectal bleeding score
    Units: points
        arithmetic mean (standard deviation)
    		 1.2 ± 0.54 1.2 ± 0.58 -
    Endoscopic Response Score
    Units: points
        arithmetic mean (standard deviation)
    		 2.7 ± 0.47 2.6 ± 0.48 -
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) analysis set comprised all randomised subjects.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set comprised all subjects who received at least 1 dose of investigational medicinal product (IMP), and was analysed according to actual treatment received.

    Subject analysis sets values
    		 Intention-to-treat Safety Analysis Set
    Number of subjects
    228
    228
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    212
    212
        From 65-84 years
    64
    64
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.5 ± 13.42
    42.5 ± 13.42
    Gender categorical
    Units: Subjects
        Female
    121
    121
        Male
    107
    107
    Race
    Units: Subjects
        American Indian or Alaska Native
    8
    8
        Asian
    3
    3
        Black or African American
    9
    9
        White
    208
    208
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    18
    18
        Not Hispanic or Latino
    210
    210
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    24.66 ± 4.552
    24.66 ± 4.552
    Stool frequency score
    Units: points
        arithmetic mean (standard deviation)
    1.7 ± 0.80
    1.7 ± 0.80
    Rectal bleeding score
    Units: points
        arithmetic mean (standard deviation)
    1.2 ± 0.55
    1.2 ± 0.55
    Endoscopic Response Score
    Units: points
        arithmetic mean (standard deviation)
    2.7 ± 0.47
    2.7 ± 0.47

    End points

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    End points reporting groups
    Reporting group title
    Mesalamine
    Reporting group description
    		 Mesalamine 4 g extended release granules (sachet), administered orally QD

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 4 g to match mesalamine extended release granules, administered orally QD
    Reporting group title
    Mesalamine (Open-Label)
    Reporting group description
    		 Mesalamine 4 g extended release granules (sachet), administered orally QD

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) analysis set comprised all randomised subjects.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set comprised all subjects who received at least 1 dose of investigational medicinal product (IMP), and was analysed according to actual treatment received.

    Primary: Proportion of Subjects With Remission

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    End point title
    		 Proportion of Subjects With Remission
    End point description
    The proportion of subjects with remission was defined by the Clinical and Endoscopic Response Score: 0 for rectal bleeding; 0 or 1 with at least 1 point decrease from baseline for stool frequency; 0 or 1 for endoscopic score. The Clinical and Endoscopic Response Score ranged between 0-9, higher scores indicating greater disease severity. This score had two components: Clinical Response which assessed subject’s symptoms and ranged between 0-6, and Endoscopic Response which assessed objective evidence of inflammation and ranged between 0-3. Further, the Clinical Response component included two subscales: stool frequency and rectal bleeding (each ranged between 0-3 each) obtained from subjects' daily records. The Endoscopic Response component had one subscale: flexible sigmoidoscopy/colonoscopy (ranging between 0-3).
    End point type
    Primary
    End point timeframe
    At Week 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114
    Units: Counts of subjects
    19
    13
    Statistical analysis title
    		 Primary endpoint analysis
    Statistical analysis description
    Proportions were compared between treatment groups, at a two-sided 0.05 significance level.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [1]
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 3.32
    Notes
    [1] - The p-value was based on chi-square test without a continuity correction.

    Secondary: Proportion of Subjects With Remission in the Primary Endpoint and the Physician's Global Assessment (PGA) score of ≤ 1 (Modified Mayo Score)

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    End point title
    		 Proportion of Subjects With Remission in the Primary Endpoint and the Physician's Global Assessment (PGA) score of ≤ 1 (Modified Mayo Score)
    End point description
    The Modified Mayo score was calculated as the sum of the Clinical and Endoscopic Response Score (Range: 0-9) and the standard PGA score (range: 0-3; normal [score=0], mild disease [score=1], moderate disease [score=2], severe disease [score=3]). The statistical test was to be conducted only if the primary analysis was significant.
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114
    Units: Counts of subjects
    19
    11
    No statistical analyses for this end point

    Secondary: Time to Cessation of Rectal Bleeding

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    End point title
    		 Time to Cessation of Rectal Bleeding
    End point description
    Defined as time in days from randomization to the first day of 3 consecutive days with a rectal bleeding score of 0, based on subject's daily diary. The statistical test was to be conducted only if the primary analysis was significant.
    End point type
    Secondary
    End point timeframe
    Up to Week 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114 [2]
    Units: Days
        median (confidence interval 95%)
    18.0 (13.0 to 30.0)
    43.0 (23.0 to 99999)
    Notes
    [2] - CIs for placebo group are not valid values. System limitations do not allow NE for not estimable
    No statistical analyses for this end point

    Secondary: The Proportion of Subjects With Endoscopic Improvement

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    End point title
    		 The Proportion of Subjects With Endoscopic Improvement
    End point description
    Defined as an Endoscopic Response Score of 0 or 1, with at least a 1 point reduction from baseline in the endoscopic score at Week 8.
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114
    Units: Number of subjects
    34
    22
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Proportions were compared between treatment groups at a two-sided 0.05 significance level.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [3]
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 3.29
    Notes
    [3] - The p-value was based on chi-square test without a continuity correction.

    Secondary: The Proportion of Subjects in Clinical Remission at Weeks 2, 4, and 8

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    End point title
    		 The Proportion of Subjects in Clinical Remission at Weeks 2, 4, and 8
    End point description
    Defined as a score of 0 for rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool frequency in the Clinical Response Score subset.
    End point type
    Secondary
    End point timeframe
    At Week 2, 4, and 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114
    Units: Number of subjects
        Week 2
    19
    17
        Week 4
    29
    26
        Week 8
    40
    28
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Proportions were compared between treatment groups over 8 weeks, at a two-sided 0.05 significance level.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Generalised estimating equation approach
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 2.15

    Secondary: Time to Normal Stool Pattern

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    End point title
    		 Time to Normal Stool Pattern
    End point description
    Defined as time in days from randomization to the first day of 3 consecutive days with a stool frequency score of 0, based on subject daily diary.
    End point type
    Secondary
    End point timeframe
    Up to Week 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114 [4]
    114 [5]
    Units: Days
        median (confidence interval 95%)
    55.0 (35.0 to 99999)
    99 (99 to 99999)
    Notes
    [4] - CIs for mesalamine are not valid values. System limitations do not allow NE for not estimable.
    [5] - CIs and mean for placebo are not valid values. System limitations do not allow NE for not estimable
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Times to normal stool pattern were compared between treatment groups, at a two-sided 0.05 significance level.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 2.02
    Notes
    [6] - The p-value was based on log-rank test.

    Secondary: The Change From Baseline in Rectal Bleeding Score at Weeks 2, 4, and 8

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    End point title
    		 The Change From Baseline in Rectal Bleeding Score at Weeks 2, 4, and 8
    End point description
    Defined as change from baseline in rectal bleeding score at Weeks 2, 4, and 8 based on subject daily diary.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 2, 4, and 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114
    Units: points
    number (not applicable)
        Week 2
    -0.39
    -0.23
        Week 4
    -0.56
    -0.31
        Week 8
    -0.64
    -0.33
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Change from baseline scores were compared between treatment groups over 8 weeks, at a two-sided 0.05 significance level.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Repeated Measures ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 -0.08

    Secondary: The Change From Baseline in Serum C-reactive Protein (CRP) Levels at Weeks 2, 4, and 8

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    End point title
    		 The Change From Baseline in Serum C-reactive Protein (CRP) Levels at Weeks 2, 4, and 8
    End point description
    The adjusted mean changes in serum CRP levels from baseline and the difference between treatment groups are presented for each time point.
    End point type
    Secondary
    End point timeframe
    From baseline up to Week 2, 4, and 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114
    Units: mg/L
    number (not applicable)
        Week 2
    -0.26
    1.07
        Week 4
    -1.62
    -0.08
        Week 8
    -2.41
    1.90
    Statistical analysis title
    		 Secondary endpoint Analysis
    Statistical analysis description
    Change from baseline scores were compared between treatment groups over 8 weeks, at a two-sided 0.05 significance level.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Repeated-measures ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -2.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.46
         upper limit
    		 0.67

    Secondary: The Change From Baseline in Fecal Calprotectin Levels at Week 8

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    End point title
    		 The Change From Baseline in Fecal Calprotectin Levels at Week 8
    End point description
    The adjusted mean change from baseline in fecal calprotectin levels at Week 8 are presented.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114
    Units: ug/g
        number (not applicable)
    -263.95
    25.74
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Changes from baseline were compared between treatment groups, at a two-sided 0.05 significance level.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -289.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -514.96
         upper limit
    		 -64.42

    Secondary: The Change From Baseline in Health Related Quality of Life (QoL) score

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    End point title
    		 The Change From Baseline in Health Related Quality of Life (QoL) score
    End point description
    The change from baseline to Week 2, 4, and 8 in Inflammatory Bowel Disease Questionnaire (IBDQ) scores. The adjusted changes from baseline and their differences between treatment groups are presented. The IBDQ is an instrument used to assess quality of life in adult patients with UC. Subjects were asked to recall symptoms and QoL from last two weeks and to rate each item on a 7-point Likert score (higher scores equate to higher QoL).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 2, 4, and 8
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    114
    114
    Units: point
    number (not applicable)
        Week 2
    25.97
    17.38
        Week 4
    34.74
    23.46
        Week 8
    36.27
    17.74
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Change from baseline scores were compared between treatment groups over 8 weeks, at a two-sided 0.05 significance level.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Repeated measures ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    12.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.1
         upper limit
    		 20.5

    Secondary: Incidence of Adverse Events

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    End point title
    		 Incidence of Adverse Events
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a subject taking part in a clinical trial. A ‘treatment-emergent AE (TEAE)' is defined as an AE which occurs in the time interval from initial dosing (IMP intake) to the end of treatment visit. Proportion of subjects with any TEAE (serious or non-serious) are presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Mesalamine Placebo Mesalamine (Open-Label)
    Number of subjects analysed
    114
    114
    170
    Units: Count of Participants
        Any TEAE
    28
    37
    31
        Serious AE
    1
    0
    2
    No statistical analyses for this end point

    Secondary: Severity of Adverse Events

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    End point title
    		 Severity of Adverse Events
    End point description
    The proportion of subjects with intensity of AEs (classified as mild, moderate or severe) are presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Mesalamine Placebo Mesalamine (Open-Label)
    Number of subjects analysed
    114
    114
    170
    Units: Number of subjects
        Mild
    23
    27
    21
        Moderate
    6
    15
    11
        Severe
    5
    3
    1
    No statistical analyses for this end point

    Secondary: Proportion of Subject With Abnormal Laboratory Values (Haematology)

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    End point title
    		 Proportion of Subject With Abnormal Laboratory Values (Haematology)
    End point description
    Proportion of subjects with markedly abnormal changes from baseline in haematology values are presented. Laboratory value (Low/Normal/High) to abnormal: Subjects in Mesalamine; Placebo; Mesalamine (Open-Label) group: Eosinophils/Leucocytes (Leuc) (%), Normal>=10: 108;108;165 Erythrocytes (10^6/uL), Low<=3.5: 10;11;15 Erythrocytes (10^6/uL), Normal<=3.5: 101; 98; 153 Haematocrit (%), Low<=0.32: 13;11;20 Haematocrit (%), Normal<=0.32; 98;98;147 Haematocrit (%), Normal>=0.56; 98;98;147 Haemoglobin (Hb) (g/dL), Low<=115: 35;35;53 Hb (g/dL), Normal<=115: 78;75;117 Leuc(10^3/uL), Normal <=2.8: 103; 104; 155 Leuc(10^3/uL), Normal >=16.0: 103; 104; 155 Leuc(10^3/uL), High>=16.0: 8;5;12 Lymphocytes (Lymp)/Leuc (%), Low<=10: 22;25;35 Lymp/Leuc (%), Normal<=10: 90;84;133 Lymp/Leuc (%), High>=80: 1;1;2 Neutrophils (Neut)/Leuc (%), Normal <=15: 98;93;148 Neut/Leuc (%), Normal >=90: 98;93;148 Neut/Leuc (%), High >=90: 15;17; 22 Platelets (10^3/uL), High>=700: 19; 22; 34
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Mesalamine Placebo Mesalamine (Open-Label)
    Number of subjects analysed
    114
    114
    170
    Units: number
    number (not applicable)
        Eosinophils/Leucocytes (%), Normal>=10 to Abnormal
    0
    2
    4
        Erythrocytes (10^6/uL), Low<=3.5 to Abnormal
    2
    4
    4
        Erythrocytes (10^6/uL), Normal<=3.5 to Abnormal
    1
    0
    2
        Haematocrit (%), Low<=0.32 to Abnormal
    4
    1
    5
        Haematocrit (%), Normal<=0.32 to Abnormal
    0
    3
    4
        Haematocrit (%), Normal>=0.56 to Abnormal
    0
    1
    0
        Haemoglobin (g/dL), Low<=115 to Abnormal
    21
    23
    37
        Haemoglobin (g/dL), Normal<=115 to Abnormal
    12
    15
    29
        Leucocytes (10^3/uL), Normal <=2.8 to Abnormal
    1
    0
    2
        Leukocytes (10^3/uL), Normal >=16.0 to Abnormal
    0
    2
    2
        Leucocytes (10^3/uL), High >=16.0 to Abnormal
    0
    1
    1
        Lymphocytes/Leucocytes (%), Low<=10 to Abnormal
    0
    3
    1
        Lymphocytes/Leucocytes (%), Normal<=10 to Abnormal
    4
    2
    6
        Lymphocytes/Leucocytes (%), High>=80 to Abnormal
    1
    0
    1
        Neutrophils/Leucocyte (%), Normal<=15 to Abnormal
    2
    0
    2
        Neutrophils/Leucocyte (%), Normal>=90 to Abnormal
    0
    1
    2
        Neutrophils/Leucocyte (%), High >=90 to Abnormal
    0
    1
    1
        Platelets (10^3/uL), High>=700 to Abnormal
    2
    0
    2
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Abnormal Laboratory Values (Coagulation)

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    End point title
    		 Proportion of Subjects With Abnormal Laboratory Values (Coagulation)
    End point description
    Proportion of subjects with markedly abnormal changes from baseline values in coagulation laboratory values are presented. INR= International normalised ratio. Laboratory value (Low/Normal/High) to abnormal: Subjects in Mesalamine; Placebo; Mesalamine (Open-Label) group: Prothrombin INR, Normal <0.8: 81; 80; 127 Prothrombin INR, Normal >1.1: 81; 80; 127 Prothrombin INR, High >1.1: 20; 22; 40
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Mesalamine Placebo Mesalamine (Open-Label)
    Number of subjects analysed
    114
    114
    170
    Units: Counts of participants
        Prothrombin INR, Normal <0.8 to Abnormal
    0
    0
    1
        Prothrombin INR, Normal >1.1 to Abnorma
    14
    14
    28
        Prothrombin INR, High >1.1 to Abnormal
    4
    10
    22
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Abnormal Laboratory Values (Serum Chemistry)

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    End point title
    		 Proportion of Subjects With Abnormal Laboratory Values (Serum Chemistry)
    End point description
    Proportion of subjects with markedly abnormal changes in serum chemistry laboratory values are presented. ALT=Alanine aminotransferase; AST=Aspartate aminotransferase; BUN=Blood urea nitrogen; GGT=Gamma glutamyl transferase. Laboratory value (Low/Normal/High) to abnormal: Subjects in Mesalamine; Placebo; Mesalamine (Open-Label) group: ALT (U/L), Normal >3xULN: 110;108;169 AST (U/L), Normal >3xULN: 107;107;163 AST (U/L), High >3xULN: 5;5;7 Bilirubin (mg/dL), Normal >=1.5xULN: 106;100;157 Bilirubin (mg/dL), High >=1.5xULN: 7;10;13 BUN (mg/dL), Normal >=10.7: 102;92;145 Calcium (mg/dL), Normal <=1.8: 110;104;162 Chloride (mmol/L), Normal >=115: 94; 98; 146 Chloride (mmol/L), High >=115: 18; 12;23 GGT (U/L), High >3xULN: 13;10;16 Glucose (mg/dL),Normal >=10: 94; 85;134 Glucose (mg/dL),High >=10: 13; 20; 25 Potassium (mmol/L), Normal <=3.0: 107; 110; 166 Potassium (mmol/L),Normal >=5.8: 107; 110; 166 Potassium (mmol/L), High >=5.8: 5;2;3 Sodium (mmol/L), Low<=130: 1;1;1
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Mesalamine Placebo Mesalamine (Open-Label)
    Number of subjects analysed
    114
    114
    170
    Units: Subjects
        ALT (U/L), Normal >3xULN to Abnormal
    1
    0
    2
        AST (U/L), Normal >3xULN to Abnormal
    1
    0
    2
        AST (U/L), High >3xULN to Abnormal
    0
    0
    1
        Bilirubin (mg/dL), Normal >=1.5xULN to Abnormal
    1
    0
    1
        Bilirubin (mg/dL), High >=1.5xULN to Abnormal
    2
    1
    4
        BUN (mg/dL), Normal >=10.7 to Abnormal
    0
    1
    1
        Calcium (mg/dL), Normal <=1.8 to Abnormal
    1
    0
    1
        Chloride (mmol/L), Normal >=115 to Abnormal
    1
    0
    1
        Chloride (mmol/L), High >=115 to Abnormal
    1
    0
    1
        GGT (U/L), High >3xULN to Abnormal
    2
    2
    4
        Glucose (mg/dL), Normal >=10 to Abnormal
    1
    1
    1
        Glucose (mg/dL), High >=10 to Abnormal
    0
    2
    1
        Potassium (mmol/L), Normal <=3.0 to Abnormal
    1
    0
    1
        Potassium (mmol/L), Normal >=5.8 to Abnormal
    1
    0
    3
        Potassium (mmol/L), High >=5.8 to Abnormal
    0
    0
    1
        Sodium (mmol/L), Low<=130 to Abnormal
    0
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAE occurred in the time interval from initial dosing (IMP intake) to the end of trial visit.
    Adverse event reporting additional description
    TEAEs were defined as AE which occurred in the time interval from initial dosing (IMP intake) to the end of treatment visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Mesalamine
    Reporting group description
    		 Mesalamine 4 g extended release granules (sachet), administered orally QD

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 4 g to match mesalamine extended release granules, administered orally QD

    Reporting group title
    Mesalamine (Open-Label)
    Reporting group description
    		 Mesalamine 4 g extended release granules (sachet), administered orally QD

    Serious adverse events
    		 Mesalamine Placebo Mesalamine (Open-Label)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    2 / 170 (1.18%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Spondylitis
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Tracheitis
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Mesalamine Placebo Mesalamine (Open-Label)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 114 (16.67%)
    13 / 114 (11.40%)
    8 / 170 (4.71%)
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    6 / 114 (5.26%)
    1 / 114 (0.88%)
    0 / 170 (0.00%)
         occurrences all number
    6
    1
    0
    Faecal calprotectin increased
         subjects affected / exposed
    5 / 114 (4.39%)
    2 / 114 (1.75%)
    4 / 170 (2.35%)
         occurrences all number
    5
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 114 (2.63%)
    2 / 114 (1.75%)
    0 / 170 (0.00%)
         occurrences all number
    3
    3
    0
    Leukocytosis
         subjects affected / exposed
    1 / 114 (0.88%)
    3 / 114 (2.63%)
    0 / 170 (0.00%)
         occurrences all number
    1
    3
    0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    3 / 114 (2.63%)
    10 / 114 (8.77%)
    4 / 170 (2.35%)
         occurrences all number
    3
    10
    4
    Diarrhoea
         subjects affected / exposed
    1 / 114 (0.88%)
    3 / 114 (2.63%)
    0 / 170 (0.00%)
         occurrences all number
    1
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2015
    This was a substantial amendment, which was implemented during the conduct of the trial. This amendment included correction of language and inconsistencies in the protocol and changes made to the planned statistical analysis.
    30 Jul 2015
    This was a substantial amendment, which was implemented during the conduct of the trial. This amendment included correction of language and inconsistencies in the protocol and additional clarifications within the methodology section of the protocol.
    11 Jan 2017
    This was a substantial amendment, which was implemented during the conduct of the trial. This amendment included clarification of language and procedures related to primary and secondary endpoints, methodology, exclusion criteria, video submission of flexible sigmoidoscopy/colonoscopy and additional clarifications within the protocol. With this amendment, the definition of remission used for analysis of the primary endpoint was changed from ‘rectal bleeding and stool frequency scores of 0 with an endoscopic score of 0 or 1 in the Clinical and Endoscopic Response Score’, to ‘rectal bleeding score of 0 and stool frequency score of 0 or 1 with at least 1 point decrease from baseline, with an endoscopic score of 0 or 1 in the Clinical and Endoscopic Response Score.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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